Solid state forms of mavacamten and process for preparation thereof

ABSTRACT

The present disclosure encompasses solid state forms of Mavacamten, in embodiments crystalline polymorphs of Mavacamten, processes for preparation thereof, and pharmaceutical compositions thereof.

FIELD OF THE DISCLOSURE

The present disclosure encompasses solid state forms of Mavacamten, inembodiments crystalline polymorphs of Mavacamten, processes forpreparation thereof, and pharmaceutical compositions thereof.

BACKGROUND OF THE DISCLOSURE

Mavacamten,6-{[(1S)-1-phenylethyl]amino}-3-(propan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione,has the following chemical structure:

Mavacamten is developed for the treatment of obstructive hypertrophiccardiomyopathy (oHCM).

The compound is described in U.S. Pat. No. 9,181,200.

Polymorphism, the occurrence of different crystalline forms, is aproperty of some molecules and molecular complexes. A single moleculemay give rise to a variety of polymorphs having distinct crystalstructures and physical properties like melting point, thermal behaviors(e.g., measured by thermogravimetric analysis (“TGA”), or differentialscanning calorimetry (“DSC”)), X-ray diffraction (XRD) pattern, infraredabsorption fingerprint, and solid state (¹³C) NMR spectrum. One or moreof these techniques may be used to distinguish different polymorphicforms of a compound.

Different salts and solid state forms (including solvated forms) of anactive pharmaceutical ingredient may possess different properties. Suchvariations in the properties of different salts and solid state formsand solvates may provide a basis for improving formulation, for example,by facilitating better processing or handling characteristics, changingthe dissolution profile in a favorable direction, or improving stability(polymorph as well as chemical stability) and shelf-life. Thesevariations in the properties of different salts and solid state formsmay also offer improvements to the final dosage form, for instance, ifthey serve to improve bioavailability. Different salts and solid stateforms and solvates of an active pharmaceutical ingredient may also giverise to a variety of polymorphs or crystalline forms, which may in turnprovide additional opportunities to assess variations in the propertiesand characteristics of a solid active pharmaceutical ingredient.

Discovering new solid state forms and solvates of a pharmaceuticalproduct may yield materials having desirable processing properties, suchas ease of handling, ease of processing, storage stability, and ease ofpurification or as desirable intermediate crystal forms that facilitateconversion to other polymorphic forms. New solid state forms of apharmaceutically useful compound can also provide an opportunity toimprove the performance characteristics of a pharmaceutical product. Itenlarges the repertoire of materials that a formulation scientist hasavailable for formulation optimization, for example by providing aproduct with different properties, including a different crystal habit,higher crystallinity, or polymorphic stability, which may offer betterprocessing or handling characteristics, improved dissolution profile, orimproved shelf-life (chemical/physical stability). For at least thesereasons, there is a need for additional solid state forms (includingsolvated forms) of Mavacamten.

SUMMARY OF THE DISCLOSURE

The present disclosure provides crystalline polymorphs of Mavacamten,processes for preparation thereof, and pharmaceutical compositionsthereof. These crystalline polymorphs can be used to prepare other solidstate forms of Mavacamten, Mavacamten salts and their solid state forms.

The present disclosure also provides uses of the said solid state formsof Mavacamten in the preparation of other solid state forms ofMavacamten or salts thereof.

The present disclosure provides crystalline polymorphs of Mavacamten foruse in medicine, including for the treatment of cardiovascular disease,especially obstructive hypertrophic cardiomyopathy (oHCM).

The present disclosure also encompasses the use of crystallinepolymorphs of Mavacamten of the present disclosure for the preparationof pharmaceutical compositions and/or formulations.

In another aspect, the present disclosure provides pharmaceuticalcompositions comprising crystalline polymorphs of Mavacamten accordingto the present disclosure.

The present disclosure includes processes for preparing the abovementioned pharmaceutical compositions. The processes include combiningany one or a combination of the crystalline polymorphs of Mavacamtenwith at least one pharmaceutically acceptable excipient.

The crystalline polymorph of Mavacamten as defined herein and thepharmaceutical compositions or formulations of the crystalline polymorphof Mavacamten may be used as medicaments, such as for the treatment ofobstructive hypertrophic cardiomyopathy (oHCM). The present disclosurealso provides methods of treating obstructive hypertrophiccardiomyopathy (oHCM), by administering a therapeutically effectiveamount of any one or a combination of the crystalline polymorphs ofMavacamten of the present disclosure, or at least one of the abovepharmaceutical compositions, to a subject suffering from obstructivehypertrophic cardiomyopathy (oHCM), or otherwise in need of thetreatment.

The present disclosure also provides uses of crystalline polymorphs ofMavacamten of the present disclosure, or at least one of the abovepharmaceutical compositions, for the manufacture of medicaments fortreating e.g., obstructive hypertrophic cardiomyopathy.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a characteristic X-ray powder diffraction pattern (XRPD) ofMavacamten Form 1.

FIG. 2 shows a characteristic XRPD of Mavacamten Form 2.

FIG. 3 shows a characteristic XRPD of Mavacamten amorphous.

FIG. 4 shows a characteristic XRPD of Mavacamten Form 4.

FIG. 5 shows a characteristic XRPD of Mavacamten Form 5.

FIG. 6 shows a characteristic XRPD of Mavacamten Form 6.

FIG. 7 shows SEM image of prism-like morphology of Mavacamten Form 1,prepared according to Example 9.

FIG. 8 shows optical microscopic image of rod-like morphology ofMavacamten Form 1, prepared according to Example 10.

FIG. 9 shows SEM image of plate-like morphology of Mavacamten Form 5,prepared according to Example 11.

DETAILED DESCRIPTION OF THE DISCLOSURE

The present disclosure encompasses solid state forms of Mavacamten,including crystalline polymorphs of Mavacamten, processes forpreparation thereof, and pharmaceutical compositions thereof.

Solid state properties of Mavacamten and crystalline polymorphs thereofcan be influenced by controlling the conditions under which Mavacamtenand crystalline polymorphs thereof are obtained in solid form.

A solid state form (or polymorph) may be referred to herein aspolymorphically pure or as substantially free of any other solid state(or polymorphic) forms. As used herein in this context, the expression“substantially free of any other forms” will be understood to mean thatthe solid state form contains about 20% (w/w) or less, about 10% (w/w)or less, about 5% (w/w) or less, about 2% (w/w) or less, about 1% (w/w)or less, or about 0% of any other forms of the subject compound asmeasured, for example, by XRPD. Thus, a crystalline polymorph ofMavacamten described herein as substantially free of any other solidstate forms would be understood to contain greater than about 80% (w/w),greater than about 90% (w/w), greater than about 95% (w/w), greater thanabout 98% (w/w), greater than about 99% (w/w), or about 100% of thesubject crystalline polymorph of Mavacamten. In some embodiments of thedisclosure, the described crystalline polymorph of Mavacamten maycontain from about 1% to about 20% (w/w), from about 5% to about 20%(w/w), or from about 5% to about 10% (w/w) of one or more othercrystalline polymorph of the same Mavacamten.

Depending on which other crystalline polymorphs a comparison is made,the crystalline polymorphs of Mavacamten of the present disclosure mayhave advantageous properties selected from at least one of thefollowing: chemical purity, flowability, solubility, dissolution rate,morphology or crystal habit, stability, such as chemical stability aswell as thermal and mechanical stability with respect to polymorphicconversion, stability towards dehydration and/or storage stability, lowcontent of residual solvent, a lower degree of hygroscopicity,flowability, and advantageous processing and handling characteristicssuch as compressibility and bulk density.

A solid state form, such as a crystal form or an amorphous form, may bereferred to herein as being characterized by graphical data “as depictedin” or “as substantially depicted in” a Figure. Such data include, forexample, powder X-ray diffractograms and solid state NMR spectra. As iswell-known in the art, the graphical data potentially providesadditional technical information to further define the respective solidstate form (a so-called “fingerprint”) which cannot necessarily bedescribed by reference to numerical values or peak positions alone. Inany event, the skilled person will understand that such graphicalrepresentations of data may be subject to small variations, e.g., inpeak relative intensities and peak positions due to certain factors suchas, but not limited to, variations in instrument response and variationsin sample concentration and purity, which are well known to the skilledperson. Nonetheless, the skilled person would readily be capable ofcomparing the graphical data in the Figures herein with graphical datagenerated for an unknown crystal form and confirm whether the two setsof graphical data are characterizing the same crystal form or twodifferent crystal forms. A crystal form of Mavacamten referred to hereinas being characterized by graphical data “as depicted in” or “assubstantially depicted in” a Figure will thus be understood to includeany crystal forms of Mavacamten characterized with the graphical datahaving such small variations, as are well known to the skilled person,in comparison with the Figure.

As used herein, and unless stated otherwise, the term “anhydrous” inrelation to crystalline forms of Mavacamten, relates to a crystallineform of Mavacamten which does not include any crystalline water (orother solvents) in a defined, stoichiometric amount within the crystal.Moreover, an “anhydrous” form would generally not contain more than 1%(w/w), of either water or organic solvents as measured for example byTGA.

The term “solvate,” as used herein and unless indicated otherwise,refers to a crystal form that incorporates a solvent in the crystalstructure. When the solvent is water, the solvate is often referred toas a “hydrate.” The solvent in a solvate may be present in either astoichiometric or in a non-stoichiometric amount.

As used herein, the term “isolated” in reference to crystallinepolymorph of Mavacamten of the present disclosure corresponds to acrystalline polymorph of Mavacamten that is physically separated fromthe reaction mixture in which it is formed.

As used herein, unless stated otherwise, the XRPD measurements are takenusing copper Kα radiation wavelength 1.5418 Å. XRPD peaks reportedherein are measured using CuK α radiation, λ=1.5418 Å, typically at atemperature of 25±3° C.

A thing, e.g., a reaction mixture, may be characterized herein as beingat, or allowed to come to “room temperature” or “ambient temperature”,often abbreviated as “RT.” This means that the temperature of the thingis close to, or the same as, that of the space, e.g., the room or fumehood, in which the thing is located. Typically, room temperature is fromabout 20° C. to about 30° C., or about 22° C. to about 27° C., or about25° C.

The amount of solvent employed in a chemical process, e.g., a reactionor crystallization, may be referred to herein as a number of “volumes”or “vol” or “V.” For example, a material may be referred to as beingsuspended in 10 volumes (or 10 vol or 10V) of a solvent. In thiscontext, this expression would be understood to mean milliliters of thesolvent per gram of the material being suspended, such that suspending 5grams of a material in 10 volumes of a solvent means that the solvent isused in an amount of 10 milliliters of the solvent per gram of thematerial that is being suspended or, in this example, 50 mL of thesolvent. In another context, the term “v/v” may be used to indicate thenumber of volumes of a solvent that are added to a liquid mixture basedon the volume of that mixture. For example, adding solvent X (1.5 v/v)to a 100 ml reaction mixture would indicate that 150 mL of solvent X wasadded.

A process or step may be referred to herein as being carried out“overnight.” This refers to a time interval, e.g., for the process orstep, that spans the time during the night, when that process or stepmay not be actively observed. This time interval is from about 8 toabout 20 hours, or about 10-18 hours, in some cases about 16 hours.

As used herein, the term “reduced pressure” refers to a pressure that isless than atmospheric pressure. For example, reduced pressure is about10 mbar to about 50 mbar.

As used herein and unless indicated otherwise, the term “ambientconditions” refer to atmospheric pressure and a temperature of 22-24° C.

The present disclosure includes a crystalline polymorph of Mavacamten,designated Form 1. The crystalline Form 1 of Mavacamten may becharacterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 1 ;an X-ray powder diffraction pattern having peaks at 11.7, 16.3, 18.7,20.0 and 23.4 degrees 2-theta±0.2 degrees 2-theta; and combinations ofthese data.

Crystalline Form 1 of Mavacamten may be further characterized by anX-ray powder diffraction pattern having peaks at 11.7, 16.3, 18.7, 20.0and 23.4 degrees 2-theta±0.2 degrees 2-theta, and also having any one,two or three additional peaks selected from 17.4, 29.1 and 31.6 degrees2-theta±0.2 degrees 2-theta.

In one embodiment of the present disclosure, crystalline Form 1 ofMavacamten is isolated.

Crystalline Form 1 of Mavacamten may be anhydrous.

In other embodiment, Crystalline Form 1 of Mavacamten may becharacterized by the following cell parameters:

Space group Cell lengths/Å Cell angles P2₁2₁2₁ a = 9.444(3) α = 90 b =12.1038(19) β = 90 c = 12.664(2) γ = 90

In some embodiments of the present invention, the crystalline Form 1 ofMavacamten, as defined according to any aspect or embodiment describedherein, may be provided in a particular morphology. In particular, thecrystalline Form 1 may comprise particles having prism-like morphologyor rod-like morphology. Crystalline Form 1 having the morphology asdescribed herein provides advantageous processing characteristics and/orstability due to particles having uniform morphology.

In a further embodiment, crystalline Form 1 of Mavacamten according tothe present invention is stable when exposed to high temperatures andhigh relative humidity.

The present invention also provides a process for preparing Form 1 ofMavacamten. The process comprising:

-   -   providing Mavacamten in an organic solvent, preferably an        alcohol, particularly methanol, 2-butanol, isobutanol,        1-propanol or dimethyformamide;    -   heating up to reflux temperature; and    -   crystallizing Form 1 either by solvent evaporation under room        temperature conditions, or by cooling the solution to about 0°        C.; preferably by ice-bath.

In another aspect of the present invention, there is provided a processfor preparing a crystalline Form 1 of Mavacamten comprising providing asuspension of Mavacamten in an organic solvent, preferably an ether,more preferably, a cyclic ether, particularly tetrahydrofuran, at refluxtemperature and removing the solvent; preferably by solvent evaporationunder room temperature conditions.

The present disclosure also provides Form 2 of Mavacamten. Thecrystalline From 2 of Mavacamten may be characterized by data selectedfrom one or more of the following: an X-ray powder diffraction patternsubstantially as depicted in FIG. 2 ; an X-ray powder diffractionpattern having peaks at 7.8, 8.5, 11.2, 17.0 and 21.5 degrees2-theta±0.2 degrees 2-theta; and combinations of these data.

Crystalline Form 2 of Mavacamten may be further characterized by anX-ray powder diffraction pattern having peaks at 7.8, 8.5, 11.2, 17.0and 21.5 degrees 2-theta±0.2 degrees 2-theta, and also having any one,two, three, four or five additional peaks selected from 11.9, 15.6,23.9, 25.6 and 26.3 degrees 2-theta±0.2 degrees 2-theta.

In one embodiment of the present disclosure, crystalline Form 2 ofMavacamten is isolated.

In a further embodiment, crystalline Form 2 of Mavacamten may beanhydrous.

The present disclosure also includes a crystalline polymorph ofMavacamten, designated Form 4. The crystalline Form 4 of Mavacamten maybe characterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 4 ;an X-ray powder diffraction pattern having peaks at 11.4, 13.0, 19.3,19.7 and 23.2 degrees 2-theta±0.2 degrees 2-theta; and combinations ofthese data.

Crystalline Form 4 of Mavacamten may be further characterized by anX-ray powder diffraction pattern having peaks at 11.4, 13.0, 19.3, 19.7and 23.2 degrees 2-theta 0.2 degrees 2-theta, and also having any one,two, three or four additional peaks selected from 12.0, 13.5, 17.1 and18.6 degrees 2-theta±0.2 degrees 2-theta.

In one embodiment of the present disclosure, crystalline Form 4 ofMavacamten is isolated.

In a further embodiment, crystalline Form 4 of Mavacamten may beanhydrous.

In a further embodiment, crystalline Form 4 of Mavacamten may becharacterized by the following cell parameters:

Space group Cell lengths/Å Cell angles P2₁2₁2₁ a = 9.8539(9) α = 90 b =12.6322(10) β = 90 c = 24.2808(17) γ = 90

The present disclosure also provides a crystalline polymorph ofMavacamten, designated Form 5. The crystalline Form 5 of Mavacamten maybe characterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 5 ;an X-ray powder diffraction pattern having peaks at 13.4, 14.8, 21.8,23.8 and 24.6 degrees 2-theta±0.2 degrees 2-theta; and combinations ofthese data.

Crystalline Form 5 of Mavacamten may be further characterized by anX-ray powder diffraction pattern having peaks at 13.4, 14.8, 21.8, 23.8and 24.6 degrees 2-theta±0.2 degrees 2-theta, and also having any one,two, three or four additional peaks selected from 11.9, 15.8, 18.9 and20.1 degrees 2-theta±0.2 degrees 2-theta.

In one embodiment of the present disclosure, crystalline Form 5 ofMavacamten is isolated.

In a further embodiment, crystalline Form 5 of Mavacamten may beanhydrous.

In another embodiment, crystalline Form 5 of Mavacamten may becharacterized by the following cell parameters:

Space group Cell lengths/Å Cell angles P2₁ a = 6.6629(6) α = 90 b =10.6505(15) β = 98.136(10) c = 10.5671(11) γ = 90

In some embodiments of the present invention, the crystalline Form 5 ofMavacamten, as defined according to any aspect or embodiment describedherein, may exhibit plate-like morphology. Crystalline Form 5 having themorphology as described herein provides advantageous processingcharacteristics and/or stability due to particles having uniformmorphology.

In a further embodiment, crystalline Form 5 of Mavacamten according tothe present invention is a stable form; i.e., it does not display solidto solid phase transformation when exposed to high temperatures and highrelative humidity.

Another aspect of the present invention relates to a process forpreparing Form 5 of Mavacamten comprising:

-   -   providing a solution of Mavacamten in an organic solvent,        preferably a monocarboxylic acid or a monocarboxylic acid amide,        particularly N,N-dimethylacetamide or acetic acid;    -   optionally, heating up to reflux temperature; and    -   crystallization of Form 5; optionally in the presence of an        anti-solvent.

In another aspect of the present invention, there is provided a processfor preparing a crystalline Form 5 of Mavacamten comprising providing asuspension of Mavacamten in an organic solvent, preferably an alkane,more preferably, a straight-chain alkane, particularly n-heptane, atelevated temperature and isolating Form 5 of Mavacamten.

The present disclosure comprises also a crystalline polymorph ofMavacamten, designated Form 6. The crystalline Form 6 of Mavacamten maybe characterized by data selected from one or more of the following: anX-ray powder diffraction pattern substantially as depicted in FIG. 6 ;an X-ray powder diffraction pattern having peaks at 6.4, 9.3, 12.7, 13.3and 20.8±0.2 degrees two-theta; and combinations of these data.

Form 6 of Mavacamten may be anhydrous.

The above crystalline polymorphs can be used to prepare othercrystalline polymorphs of Mavacamten, Mavacamten salts and their solidstate forms.

The present disclosure encompasses a process for preparing other solidstate forms of Mavacamten, Mavacamten salts and their solid state formsthereof. The process for preparing salts of Mavacamten includesacidifying any one or a combination of the above described solid stateforms of Mavacamten to obtain the corresponding salt.

The present disclosure also encompasses the use of crystallinepolymorphs of Mavacamten of the present disclosure for the preparationof pharmaceutical compositions of crystalline polymorph Mavacamtenand/or crystalline polymorphs thereof.

The present disclosure includes processes for preparing the abovementioned pharmaceutical compositions. The processes include combiningany one or a combination of the crystalline polymorphs of Mavacamten ofthe present disclosure with at least one pharmaceutically acceptableexcipient.

Pharmaceutical combinations or formulations of the present disclosurecontain any one or a combination of the solid state forms of Mavacamtenof the present disclosure. In addition to the active ingredient, thepharmaceutical formulations of the present disclosure can contain one ormore excipients. Excipients are added to the formulation for a varietyof purposes.

Diluents increase the bulk of a solid pharmaceutical composition, andcan make a pharmaceutical dosage form containing the composition easierfor the patient and caregiver to handle. Diluents for solid compositionsinclude, for example, microcrystalline cellulose (e.g., Avicel®),microfine cellulose, lactose, starch, pregelatinized starch, calciumcarbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasiccalcium phosphate dihydrate, tribasic calcium phosphate, kaolin,magnesium carbonate, magnesium oxide, maltodextrin, mannitol,polymethacrylates (e.g., Eudragit®), potassium chloride, powderedcellulose, sodium chloride, sorbitol, and talc.

Solid pharmaceutical compositions that are compacted into a dosage form,such as a tablet, can include excipients whose functions include helpingto bind the active ingredient and other excipients together aftercompression. Binders for solid pharmaceutical compositions includeacacia, alginic acid, carbomer (e.g. carbopol), carboxymethylcellulosesodium, dextrin, ethyl cellulose, gelatin, guar gum, hydrogenatedvegetable oil, hydroxyethyl cellulose, hydroxypropyl cellulose (e.g.Klucel®), hydroxypropyl methyl cellulose (e.g. Methocel®), liquidglucose, magnesium aluminum silicate, maltodextrin, methylcellulose,polymethacrylates, povidone (e.g. Kollidon®, Plasdone®), pregelatinizedstarch, sodium alginate, and starch.

The dissolution rate of a compacted solid pharmaceutical composition inthe patient's stomach can be increased by the addition of a disintegrantto the composition. Disintegrants include alginic acid,carboxymethylcellulose calcium, carboxymethylcellulose sodium (e.g.,Ac-Di-Sol®, Primellose®), colloidal silicon dioxide, croscarmellosesodium, crospovidone (e.g., Kollidon®, Polyplasdone®), guar gum,magnesium aluminum silicate, methyl cellulose, microcrystallinecellulose, polacrilin potassium, powdered cellulose, pregelatinizedstarch, sodium alginate, sodium starch glycolate (e.g., Explotab®), andstarch.

Glidants can be added to improve the flowability of a non-compactedsolid composition and to improve the accuracy of dosing. Excipients thatcan function as glidants include colloidal silicon dioxide, magnesiumtrisilicate, powdered cellulose, starch, talc, and tribasic calciumphosphate.

When a dosage form such as a tablet is made by the compaction of apowdered composition, the composition is subjected to pressure from apunch and dye. Some excipients and active ingredients have a tendency toadhere to the surfaces of the punch and dye, which can cause the productto have pitting and other surface irregularities. A lubricant can beadded to the composition to reduce adhesion and ease the release of theproduct from the dye. Lubricants include magnesium stearate, calciumstearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenatedcastor oil, hydrogenated vegetable oil, mineral oil, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate,stearic acid, talc, and zinc stearate.

Flavoring agents and flavor enhancers make the dosage form morepalatable to the patient. Common flavoring agents and flavor enhancersfor pharmaceutical products that can be included in the composition ofthe present disclosure include maltol, vanillin, ethyl vanillin,menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.

Solid and liquid compositions can also be dyed using anypharmaceutically acceptable colorant to improve their appearance and/orfacilitate patient identification of the product and unit dosage level.

In liquid pharmaceutical compositions of the present invention,Mavacamten and any other solid excipients can be dissolved or suspendedin a liquid carrier such as water, vegetable oil, alcohol, polyethyleneglycol, propylene glycol, or glycerin.

Liquid pharmaceutical compositions can contain emulsifying agents todisperse uniformly throughout the composition an active ingredient orother excipient that is not soluble in the liquid carrier. Emulsifyingagents that can be useful in liquid compositions of the presentinvention include, for example, gelatin, egg yolk, casein, cholesterol,acacia, tragacanth, chondrus, pectin, methyl cellulose, carbomer,cetostearyl alcohol, and cetyl alcohol.

Liquid pharmaceutical compositions of the present invention can alsocontain a viscosity enhancing agent to improve the mouth-feel of theproduct and/or coat the lining of the gastrointestinal tract. Suchagents include acacia, alginic acid bentonite, carbomer,carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methylcellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose,hydroxypropyl cellulose, hydroxypropyl methyl cellulose, maltodextrin,polyvinyl alcohol, povidone, propylene carbonate, propylene glycolalginate, sodium alginate, sodium starch glycolate, starch tragacanth,xanthan gum and combinations thereof.

Sweetening agents such as sorbitol, saccharin, sodium saccharin,sucrose, aspartame, fructose, mannitol, and invert sugar can be added toimprove the taste.

Preservatives and chelating agents such as alcohol, sodium benzoate,butylated hydroxyl toluene, butylated hydroxyanisole, andethylenediamine tetraacetic acid can be added at levels safe foringestion to improve storage stability.

According to the present disclosure, a liquid composition can alsocontain a buffer such as gluconic acid, lactic acid, citric acid, oracetic acid, sodium gluconate, sodium lactate, sodium citrate, or sodiumacetate. Selection of excipients and the amounts used can be readilydetermined by the formulation scientist based upon experience andconsideration of standard procedures and reference works in the field.

The solid compositions of the present disclosure include powders,granulates, aggregates, and compacted compositions. The dosages includedosages suitable for oral, buccal, rectal, parenteral (includingsubcutaneous, intramuscular, and intravenous), inhalant, and ophthalmicadministration. Although the most suitable administration in any givencase will depend on the nature and severity of the condition beingtreated, in embodiments the route of administration is oral. The dosagescan be conveniently presented in unit dosage form and prepared by any ofthe methods well-known in the pharmaceutical arts.

Dosage forms include solid dosage forms like tablets, powders, capsules,suppositories, sachets, troches, and lozenges, as well as liquid syrups,suspensions, and elixirs.

The dosage form of the present disclosure can be a capsule containingthe composition, such as a powdered or granulated solid composition ofthe disclosure, within either a hard or soft shell. The shell can bemade from gelatin and optionally contain a plasticizer such as glycerinand/or sorbitol, an opacifying agent and/or colorant.

The active ingredient and excipients can be formulated into compositionsand dosage forms according to methods known in the art.

A composition for tableting or capsule filling can be prepared by wetgranulation. In wet granulation, some or all of the active ingredientsand excipients in powder form are blended and then further mixed in thepresence of a liquid, typically water, that causes the powders to clumpinto granules. The granulate is screened and/or milled, dried, and thenscreened and/or milled to the desired particle size. The granulate canthen be tableted, or other excipients can be added prior to tableting,such as a glidant and/or a lubricant.

A tableting composition can be prepared conventionally by dry blending.For example, the blended composition of the actives and excipients canbe compacted into a slug or a sheet and then comminuted into compactedgranules. The compacted granules can subsequently be compressed into atablet.

As an alternative to dry granulation, a blended composition can becompressed directly into a compacted dosage form using directcompression techniques. Direct compression produces a more uniformtablet without granules. Excipients that are particularly well suitedfor direct compression tableting include microcrystalline cellulose,spray dried lactose, dicalcium phosphate dihydrate, and colloidalsilica. The proper use of these and other excipients in directcompression tableting is known to those in the art with experience andskill in particular formulation challenges of direct compressiontableting.

A capsule filling of the present disclosure can include any of theaforementioned blends and granulates that were described with referenceto tableting, but they are not subjected to a final tableting step.

Mavacamten may be formulated for administration to a mammal, inembodiments to a human, by injection. Mavacamten can be formulated, forexample, as a viscous liquid solution or suspension, such as a clearsolution, for injection. The formulation can contain one or moresolvents. A suitable solvent can be selected by considering thesolvent's physical and chemical stability at various pH levels,viscosity (which would allow for syringeability), fluidity, boilingpoint, miscibility, and purity. Suitable solvents include alcohol USP,benzyl alcohol NF, benzyl benzoate USP, and Castor oil USP. Additionalsubstances can be added to the formulation such as buffers,solubilizers, and antioxidants, among others. Ansel et al.,Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th ed.

The crystalline polymorphs of Mavacamten and the pharmaceuticalcompositions and/or formulations of Mavacamten of the present disclosurecan be used as medicaments, in embodiments in the treatment ofobstructive hypertrophic cardiomyopathy (oHCM).

The present disclosure also provides methods of treating obstructivehypertrophic cardiomyopathy by administering a therapeutically effectiveamount of any one or a combination of the crystalline polymorphs ofMavacamten of the present disclosure, or at least one of the abovepharmaceutical compositions and/or formulations, to a subject in need ofthe treatment.

Having thus described the disclosure with reference to particularpreferred embodiments and illustrative examples, those in the art canappreciate modifications to the disclosure as described and illustratedthat do not depart from the spirit and scope of the disclosure asdisclosed in the specification. The Examples are set forth to aid inunderstanding the disclosure but are not intended to, and should not beconstrued to limit its scope in any way.

Powder X-ray Diffraction (“XRPD”) Method

Sample, after being powdered in a mortar and pestle, is applied directlyon a silicon plate holder. The X-ray powder diffraction pattern wasmeasured with Philips X'Pert PRO X-ray powder diffractometer, equippedwith Cu irradiation source=1.54184 {acute over (Å)} ({acute over(Å)}ngström), X'Celerator (2.022° 2θ) detector. Scanning parameters:angle range: 3-40 deg., step size 0.0167, time per step 37 s, continuousscan. The described peak positions were determined using silicon powderas an internal standard.

SEM Method:

SEM micrographs were taken on Joel JSM-5800 scanning microscope at 20kV, WD 20-22, low current. Samples were sputtered with gold by EdwardsS150 sputter coater.

Optical Microscope:

Samples were analyzed on Olympus BX53 optical microscope with cameraOlympus XC50, using silicon oil as dispersion medium.

Sinale-Crystal X-Ray Diffraction (“SCXRD”) Method

A suitable crystal was selected and mounted directly on the goniometerof Xcalibur, Sapphire3, Gemini diffractometer. The crystal was kept at298 K during data collection. Data collection was carried out usingCrysAlis Pro (Rigaku Oxford Diffraction). Using Olex2¹, the structurewas solved with the SHELXT² structure solution program using IntrinsicPhasing and refined with the SHELXL³ refinement package using LeastSquares minimisation. ¹ Dolomanov, O. V., Bourhis, L. J., Gildea, R. J,Howard, J. A. K. & Puschmann, H. (2009), J. Appl. Cryst. 42, 339-341.²Shedrick, G. M. (2015). Acta Cryst. A71, 3-8.³ Sheldrick, G. M. (2015).Acta Cryst. C71, 3-8.

EXAMPLES Preparation of Starting Materials

Mavacamten can be prepared according to methods known from theliterature, for example U.S. Pat. No. 9,181,200 (Example 1).

Example 1: Preparation of Mavacamten Form 1

Mavacamten (50 mg) was dissolved in methanol (2 ml) at refluxtemperature. Prepared solution was left open at room conditions forsolvent to evaporate. After crystallization occurred, crystals werefiltrated off and analyzed by XRPD. Form 1 of Mavacamten was obtained,as shown FIG. 1 .

Example 2: Preparation of Mavacamten Form 2

Mavacamten (Form 1, 50 mg) was heated from 30° C. to 241° C. at 10°C./step and heating rate 10° C./min and then cooled to 30° C. The sampletemperature was controlled using Anton Paar TCU100 Temperature ControlUnit. Sample was analyzed by XRPD. Form 2 of Mavacamten was obtained, asshown in FIG. 2 .

Example 3: Preparation of Mavacamten Amorphous

Mavacamten (2.0 grams) was dissolved in absolute ethanol (90 ml) byheating to 52° C. Prepared solution was then spray dried at followingconditions: T(inlet=100°) C, Aspiration=35 m³ h⁻¹ and Pump rate=6.9ml/min. Obtained material was analyzed by XRPD. Amorphous was obtained,as shown in FIG. 3 .

Example 4: Preparation of Mavacamten Form 4

Amorphous Mavacamten (20 mg) was exposed to atmosphere vapor ofcyclohexane for 7 days. The obtained product was analyzed by XRPD. Form4 of Mavacamten was obtained, as shown in FIG. 4 .

Example 5: Preparation of Mavacamten Form 5

Amorphous Mavacamten (200 mg) was suspended in n-heptane (2 ml) at 40°C. for 4 hours and additionally stirred at 20-25° C. for 16 hours.Material was isolated by vacuum filtration and analyzed by XRPD. Form 5of Mavacamten was obtained, as shown in FIG. 5 .

Example 6: Preparation of Mavacamten Form 6

Amorphous Mavacamten (20 mg) was placed in an Eppendorf tube and thetube was placed in crystallization flask with 2 mL of chloroform. Thecrystallization flask was then closed. The sample was exposed tochloroform vapors for 14 days after which the material was analyzed byXRPD. Form 6 of Mavacamten was obtained, as shown in FIG. 6 .

Example 7: Preparation of Mavacamten Form 1

Mavacamten (50 mg) was suspended in tetrahydrofuran (5 ml) at refluxtemperature. Suspension was left open at room conditions for solvent toevaporate. After crystallization occurred, crystals were filtrated offand analyzed by XRPD-Form 1 of Mavacamten was obtained.

Example 8: Preparation of Mavacamten Form 5

Mavacamten (50 mg) was dissolved in N,N-dimethylacetamide (1 ml) attemperature of 100° C. Solution was left open at room conditions forsolvent to evaporate. After crystallization occurred, crystals werefiltrated off and analyzed by XRPD-Form 5 of Mavacamten was obtained.

Example 9: Preparation of Mavacamten Form 1

Mavacamten (1 gram) was dissolved in isobutanol (30 ml) at 80° C.Obtained solution was cooled to room temperature, stirred overnight andthen additionally cooled (ice bath) for 1 hour. The obtained precipitatewas filtrated off and analyzed by XRPD-Form 1 of Mavacamten.

Example 10: Preparation of Mavacamten Form 1

Mavacamten (50 mg) was dissolved in ethanol (2 ml) at 60° C. Solutionwas left open at room conditions for solvent to evaporate. Aftercrystallization occurred, crystals were filtrated off and analyzed byXRPD-Form 1 of Mavacamten.

Example 11: Preparation of Mavacamten Form 5

Mavacamten (3 grams) was dissolved in acetic acid (25 ml) at 55° C.Obtained solution was cooled to room temperature and added dropwise intowater (100 ml). Crystals were filtrated off and analyzed by XRPD-Form 5of Mavacamten.

1. A crystalline form of Mavacamten designated as Form 1, characterizedby an X-ray powder diffraction pattern having peaks at 11.7, 16.3, 18.7,20.0 and 23.4 degrees 2-theta±0.2 degrees 2-theta.
 2. The crystallineForm 1 of Mavacamten according to claim 1, characterized by an XRPDhaving peaks at: 11.7, 16.3, 18.7, 20.0 and 23.4 degrees 2-theta±0.2degrees 2-theta; and further characterized by having one, two or threeadditional peaks selected from 17.4, 29.1 and 31.6 degrees 2-theta±0.2degrees 2-theta.
 3. The crystalline Form 1 of Mavacamten according toclaim 2, wherein said crystalline Form 1 is characterized by an XRPDhaving peaks at: 11.7, 16.3, 17.4, 18.7, 20.0, 23.4, 29.1 and 31.6degrees 2-theta±0.2 degrees 2-theta.
 4. The crystalline form ofMavacamten according to claim 1, characterized by the X-ray powderdiffraction pattern substantially as depicted in FIG. 1 .
 5. Thecrystalline Form 1 of Mavacamten according to claim 1, wherein said formis an anhydrous form.
 6. A crystalline form of Mavacamten designated asForm 5, characterized by an X-ray powder diffraction pattern havingpeaks at 13.4, 14.8, 21.8, 23.8 and 24.6 degrees 2-theta±0.2 degrees2-theta.
 7. The crystalline Form 5 of Mavacamten according to claim 6,wherein said crystalline is characterized by an XRPD having peaks at:13.4, 14.8, 21.8, 23.8 and 24.6 degrees 2-theta±0.2 degrees 2-theta; andfurther characterized by having one, two, three or four additional peaksselected from 11.9, 15.8, 18.9 and 20.1 degrees 2-theta±0.2 degrees2-theta.
 8. The crystalline Form 5 of Mavacamten according to claim 7,wherein said crystalline Form 5 is characterized by an XRPD having peaksat: 11.9, 13.4, 14.8, 15.8, 18.9, 20.1, 21.8, 23.8 and 24.6 degrees2-theta±0.2 degrees 2-theta.
 9. The crystalline Form 5 of Mavacamtenaccording to claim 6, characterized by the X-ray powder diffractionpattern substantially as depicted in FIG. 5 .
 10. The crystalline Form 5of Mavacamten according to claim 6, wherein said form is an anhydrousform.
 11. A pharmaceutical composition comprising the crystalline Form 1of Mavacamten according to claim 1 and at least one pharmaceuticallyacceptable excipient.
 12. (canceled)
 13. A process for preparing thepharmaceutical composition according to claim 11, comprising combiningthe crystalline Form 1 of Mavacamten according to claim 1 with at leastone pharmaceutically acceptable excipient.
 14. A medicament comprisingthe crystalline Form 1 of Mavacamten according to claim
 1. 15.(canceled)
 16. A method of treating obstructive hypertrophiccardiomyopathy (oHCM), comprising administering a therapeuticallyeffective amount of the crystalline Form 1 of Mavacamten according toclaim 1 to a subject in need of the treatment.
 17. A pharmaceuticalcomposition comprising the crystalline Form 5 of Mavacamten according toclaim 7 and at least one pharmaceutically acceptable excipient.
 18. Aprocess for preparing a pharmaceutical composition comprising combiningthe crystalline Form 5 of Mavacamten according to claim 7 with at leastone pharmaceutically acceptable excipient.
 19. A medicament comprisingthe crystalline Form 5 of Mavacamten according to claim
 7. 20. A methodof treating obstructive hypertrophic cardiomyopathy (oHCM), comprisingadministering a therapeutically effective amount of the crystalline Form5 of Mavacamten according to claim 7 to a subject in need of thetreatment.